Rationally designed foldameric adjuvants enhance antibiotic efficacy via promoting membrane hyperpolarization. Issue 1 (11th November 2021)

• Record Type: Journal Article
• Authors: Bhaumik, Kaushik Nath; Hetényi, Anasztázia; Olajos, Gábor; Martins, Ana; Spohn, Réka; Németh, Lukács; Jojart, Balázs; Szili, Petra; Dunai, Anett; Jangir, Pramod K.; Daruka, Lejla; Földesi, Imre; Kata, Diána; Pál, Csaba; Martinek, Tamás A.
• Is Part Of: Molecular Systems Design and Engineering. Volume 7:Issue 1(2022)
• Page Start: 21
• Page End: 33
• Publication Date: 2021-11-11
• Subjects: Chemistry -- Molecular aspects -- Periodicals; Chemical engineering -- Molecular aspects -- Periodicals; Nanotechnology -- Periodicals; 620.5
• DOI: 10.1039/d1me00118c
• Languages: English
• ISSNs: 2058-9689

Abstract

Abstract : Antimicrobial foldamers reduce the antibiotic resistance in multi-drug resistant Gram-negative bacteria. They hyperpolarize the membrane at low concentrations by acting as selective ionophores, enhancing the GHK-potential across the membrane. Abstract : The negative membrane potential of bacterial cells influences crucial cellular processes. Inspired by the molecular scaffold of the antimicrobial peptide PGLa, we have developed antimicrobial foldamers with a computer-guided design strategy. The novel PGLa analogues induce sustained membrane hyperpolarization. When co-administered as an adjuvant, the resulting compounds – PGLb1 and PGLb2 – have substantially reduced the level of antibiotic resistance of multi-drug resistant Escherichia coli, Klebsiella pneumoniae and Shigella flexneri clinical isolates. The observed antibiotic potentiation was mediated by hyperpolarization of the bacterial membrane caused by the alteration of cellular ion transport. Specifically, PGLb1 and PGLb2 are selective ionophores that enhance the Goldman–Hodgkin–Katz potential across the bacterial membrane. These findings indicate that manipulating bacterial membrane electrophysiology could be a valuable tool to overcome antimicrobial resistance.